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Ocean warming and population irruptions of crown-of-thorns starfish (CoTS; Acanthaster cf. solaris) are two of the greatest threats to coral reefs. As such, there is significant interest in understanding how CoTS may be directly impacted by rising ocean temperatures. Settlement of planktonic larvae and subsequent metamorphosis is purported to be a major population bottleneck in marine invertebrates, yet it is unknown how ocean warming will impact these processes in CoTS. Herein, the effect of temperature (28 °C ambient, 30 °C, 32 °C, 34 °C) on the settlement success, metamorphic success, and post-settlement survival of this corallivore was explored. While larval settlement was robust to elevated temperature, with at least 94% of larvae settling after 48 h across all temperatures, it was observed that settlement success was lower on substrate that had been pre-treated ≥ 32 °C. Metamorphic success was also significantly constrained at temperatures ≥ 32 °C. At 32 °C and 34 °C metamorphic success was 16% and 63% lower than at ambient temperature, respectively. Significant adverse effects of warming on post-settlement survival were observed at even cooler temperatures, with 10% lower survival at 30 °C compared to at ambient temperature, and at 34 °C, survival was 34% lower. Substantial reductions in metamorphic success and early post-settlement survival at elevated temperatures, as well as negative impacts of warming on the settlement substrate and its capacity to induce settlement, may present a bottleneck for recruitment in a warmer ocean.

Rising ocean temperatures are threatening marine species and populations worldwide, and ectothermic taxa are particularly vulnerable to warming. Echinoderms are an ecologically important phylum of marine ectotherms and shifts in their population dynamics can have profound impacts on the marine environment. The effects of warming on echinoderms are highly variable across controlled laboratory-based studies. Accordingly, synthesis of these studies will facilitate the better understanding of broad patterns in responses of echinoderms to ocean warming. Herein, a meta-analysis incorporating the results of 85 studies (710 individual responses) is presented, exploring the effects of warming on various performance predictors. The mean responses of echinoderms to all magnitudes of warming were compared across multiple biological responses, ontogenetic life stages, taxonomic classes, and regions, facilitated by multivariate linear mixed effects models. Further models were conducted which only incorporated responses to warming greater than the projected end-of-century mean annual temperatures at the collection sites. This meta-analysis provides evidence that ocean warming will generally accelerate metabolic rate (+ 32%) and reduce survival (– 35%) in echinoderms, and echinoderms from sub-tropical (– 9%) and tropical (– 8%) regions will be the most vulnerable. The relatively high vulnerability of echinoderm larvae to warming (– 20%) indicates that this life stage may be a significant developmental bottleneck in the near-future, likely reducing successful recruitment into populations. Furthermore, asteroids appear to be the class of echinoderms that are most negatively affected by elevated temperature (– 30%). When considering only responses to magnitudes of warming representative of end-of-century climate change projections, the negative impacts on asteroids, tropical species and juveniles were exacerbated (– 51%, – 34%, and – 40% respectively). The results of these analyses enable better predictions of how keystone and invasive echinoderm species may perform in a warmer ocean, and the possible consequences for populations, communities, and ecosystems.

Objective The objective of this study was to evaluate patients with ganglionic acetylcholine receptor antibody (gAChR-Ab) positive autoimmune autonomic ganglionopathy using a multimodal testing protocol to characterize their full clinical phenotype and explore biomarkers to quantify immunotherapy response. Methods We conducted a cohort study of 13 individuals (7 women, 21-69 years of age) with autonomic failure and gAChR-Ab >100 pM identified between 2005 and 2019. From 2018, all patients were longitudinally assessed with cardiovascular, pupillary, urinary, sudomotor, lacrimal and salivary testing, and Composite Autonomic Symptom Score (COMPASS-31) autonomic symptom questionnaires. The orthostatic intolerance ratio was calculated by dividing change in systolic blood pressure over time tolerated on head-up tilt. Eleven patients received immunotherapy. Results At first assessment, all 13 patients had cardiovascular and pupillary impairments, 7 of 8 had postganglionic sudomotor dysfunction, 9 of 11 had urinary retention and xeropthalmia, and 6 of 8 had xerostomia. After immunotherapy, there were significant improvements in orthostatic intolerance ratio (33.3 [17.8-61.3] to 5.2 [1.4-8.2], p = 0.007), heart rate response to deep breathing (1.5 [0.0-3.3] to 4.5 [3.0-6.3], p = 0.02), pupillary constriction to light (12.0 [5.5-18.0] to 19.0 [10.6-23.8]%, p = 0.02), saliva production (0.01 [0.01-0.05] to 0.08 [0.02-0.20] g/min, p = 0.03), and COMPASS-31 scores (52 to 17, p = 0.03). Orthostatic intolerance ratio correlated with autonomic symptoms at baseline (r = 0.841, p = 0.01) and following immunotherapy (r = 0.889, p = 0.02). Immunofluorescence analyses of skin samples from a patient 32 years after disease onset showed loss of nerve fibers supplying the dermal autonomic adnexa and epidermis, with clear improvements following immunotherapy. Interpretation Patients with autoimmune autonomic ganglionopathy demonstrated objective evidence of widespread sympathetic and parasympathetic autonomic failure, with significant improvements after immunotherapy. Quantitative autonomic biomarkers should be used to define initial deficits, guide therapeutic decisions, and document treatment response. ANN NEUROL 2021;89:753-768.

Population irruptions of Pacific crown-of-thorns starfish (Acanthaster cf. solaris) have caused substantial damage to coral reefs, but it is largely unknown how this asteroid will fare in a warmer ocean. We exposed these starfish to one of four thermal treatments, with final temperatures of 26 °C (control, annual average), 28 °C (summer average), 30 °C (summer maximum) and 32 °C (predicted summer maximum by 2100). We measured the righting time, movement rate, standard metabolic rate and probability of survival of the crown-of-thorns starfish at various timepoints over ~ 60 days. We found that while temperature did not affect righting time, it did significantly affect movement rate. The movement rate of starfish increased across the 26 to 30 °C range, with those at 28 °C and 30 °C moving 18 and 27% faster than those at the control temperature. Similarly, the standard metabolic rate of starfish increased from 26 to 30 °C, with metabolism 100% and 260% faster at 28 °C and 30 °C compared to those at the 26 °C control. At 32 °C, individual starfish exhibited a 14% slower movement rate, a 33% slower metabolic rate, and also exhibited a fourfold lower probability of survival than those at 30 °C. These results indicate that 32 °C is above the thermal optimum of crown-of-thorns starfish, suggesting that prolonged exposure to temperatures that are expected to be regularly exceeded under near-future climate change may be detrimental to this species.

Purified IgG from a patient with progressive encephalopathy with rigidity and myoclonus (PERM) who had raised antibodies to the inhibitory glycine receptor was injected into mice together with lipopolysaccharide to open the blood–brain barrier. The mice developed a motor phenotype, indicated by falling off a rotating cylinder earlier than healthy IgG injected controls. At termination, these mice had deposits of IgG within the brainstem neurons which express glycine receptors, consistent with an antibody‐induced dysfunction of these neurons., Aims Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a life‐threatening condition often associated with highly raised serum antibodies to glycine receptors (GlyRs); these bind to the surface of large neurons and interneurons in rodent brain and spinal cord sections and, in vitro, inhibit function and reduce surface expression of the GlyRs. The effects in vivo have not been reported. Methods Purified plasma IgG from a GlyR antibody‐positive patient with PERM, and a healthy control (HC), was injected daily into the peritoneal cavity of mice for 12 days; lipopolysaccharide (LPS) to open the blood–brain barrier, was injected on days 3 and 8. Based on preliminary data, behavioural tests were only performed 48 h post‐LPS on days 5–7 and 10–12. Results The GlyR IgG injected mice showed impaired ability on the rotarod from days 5 to 10 but this normalized by day 12. There were no other behavioural differences but, at termination (d13), the GlyR IgG‐injected mice had IgG deposits on the neurons that express GlyRs in the brainstem and spinal cord. The IgG was not only on the surface but also inside these large GlyR expressing neurons, which continued to express surface GlyR. Conclusions Despite the partial clinical phenotype, not uncommon in passive transfer studies, the results suggest that the antibodies had accessed the GlyRs in relevant brain regions, led to antibody‐mediated internalization and increased GlyR synthesis, compatible with the temporary loss of function.

Clinical Features Which Predict Neuronal Surface Autoantibodies in New-Onset Focal Epilepsy: Implications for Immunotherapies McGinty RN, Handel A, Moloney T, et al. J Neurol Neurosurg Psychiatry. 2020;92(3):291-294. doi:10.1136/jnnp-2020-325011Objective:To generate a score which clinically identifies surface-directed autoantibodies in adults with new-onset focal epilepsy and evaluate the value of immunotherapy in this clinical setting.Methods:Prospective clinical and autoantibody evaluations in a cohort of 219 consecutive patients with new-onset focal epilepsy.Results:A total of 10.5% (23/219) of people with new-onset focal epilepsy had detectable serum autoantibodies to known or novel cell surface antigenic targets. Nine of 23 with autoantibodies were diagnosed with encephalitis, by contrast to 0/196 without autoantibodies (P < .0001). Multivariate analysis identified 6 features which predicted autoantibody positivity (area under the curve = 0.83): age ≥54 years, ictal piloerection, lowered self-reported mood, reduced attention, magnetic resonance imaging limbic system changes, and the absence of conventional epilepsy risk factors. Eleven (79%) of 14 patients with detectable autoantibodies, but without encephalitis, showed excellent long-term outcomes (modified Rankin Score = 0) despite no immunotherapy. These outcomes were superior to those of immunotherapy-treated patients with confirmed autoantibody-mediated encephalitis (P < .05).Conclusions:Seizure semiology, cognitive and mood phenotypes, alongside inflammatory investigation findings, aid the identification of surface autoantibodies among unselected people with new-onset focal epilepsy. The excellent immunotherapy-independent outcomes of autoantibody-positive patients without encephalitis suggest immunotherapy administration should be guided by clinical features of encephalitis, rather than autoantibody positivity. Our findings suggest that, in this cohort, immunotherapy-responsive seizure syndromes with autoantibodies largely fall under the umbrella of autoimmune encephalitis. Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score. de Bruijn M, Bastiaansen AEM, Mojzisova H, et al. Ann Neurol. 2021;89(4):698-710. doi:https://doi.org/10.1002/ana.26013.Objective:Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology and to create a score to preselect patients requiring testing.Methods:In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic.Results:We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2-18). Twenty (3.4%) patients had AES, of whom 3 had anti-leucine-rich glioma inactivated 1, 3 had anti-contactin-associated protein-like 2, 1 had anti-N-methyl-d-aspartate receptor, and 13 had antiglutamic acid decarboxylase 65 (enzyme-linked immunosorbent assay concentrations >10 000 IU/mL). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% CI = 19.6-3332.2, P < .0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1-56.6, P = .0005), behavioral changes (OR = 12.3, 95% CI = 3.2-49.9, P = .0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1-56.6, P = .0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4-382.7, P = .009), and speech problems (OR = 9.6, 95% CI = 2.0-46.7, P = .005). The internally validated C-statistic was 0.95 and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%.Interpretation:Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing.

To evaluate the Dutch-English Lambert-Eaton Myasthenic Syndrome (LEMS) Tumour Association Prediction (DELTA-P) score in a prospective cohort of patients with newly diagnosed LEMS to assess the clinical validity of this tool in a real-world setting. Clinical features from 87 patients with LEMS, occurring within three months from disease onset, were collated to produce a DELTA-P score for each patient. Lung cancer was detected in 44/87 (51%) LEMS patients. Weight loss ≥ 5%, tobacco use at LEMS onset and age at onset ≥ 50 years were independent predictors for the development of small-cell lung cancer (SCLC) in LEMS patients in multivariable analysis. Median DELTA-P scores were significantly higher in SCLC-LEMS patients (3.5, 95% CI 3 to 4) compared to non-tumour-LEMS (2, 95% CI 1 to 2) (P

Since approximately 50% of patients with Lambert-Eaton myasthenic syndrome (LEMS) subsequently develop small-cell lung cancer (SCLC), it is important to be able to predict cancer occurrence in these patients at neurological presentation. We aimed to determine whether circulating biomarkers were effective and objective predictors of cancer development in LEMS. We found that the presence of either SOX2, N-type voltage gated calcium channel or GABAb antibodies at LEMS diagnosis was highly sensitive (84%) and specific (87%) for the detection of SCLC. Screening for SOX2 and neuronal antibodies is a useful adjunct to clinical predictive scoring tools in predicting SCLC in LEMS.

ObjectiveTo report the prevalence of anti-neuronal antibodies in a prospective whole-nation cohort of children presenting with seizures before their third birthday.MethodsThis was a prospective population-based national cohort study involving all children presenting with new-onset epilepsy or complex febrile seizures before their third birthday over a 3-year period. Patients with previously identified structural, metabolic, or infectious cause for seizures were excluded. Serum samples were obtained at first presentation and tested for 7 neuronal antibodies using live cell-based assays. Clinical data were collected with structured proformas at recruitment and 24 months after presentation. In addition, patients with seizures and clinically suspected autoimmune encephalitis were independently identified by a review of the case records of all children ResultsTwo hundred ninety-eight patients were identified and recruited and underwent autoantibody testing. Antibody positivity was identified in 18 of 298 (6.0%). The antibodies identified were GABA receptor B (n = 8, 2.7%), contactin-associated protein 2 (n = 4, 1.3%), glycine receptor (n = 3, 1.0%), leucine-rich glioma inactivated 1 (n = 2, 0.7%), NMDA receptor (n = 1, 0.3%), and GABA receptor A (n = 1, 0.3%). None of these patients had a clinical picture of autoimmune encephalitis. Seizure classification and clinical phenotype did not correlate with antibody positivity.ConclusionsAutoimmune encephalitis is very rare in early childhood. However serum neuronal antibodies are identified in 6.4% of children presenting with seizures at

Background and aims: Acquired Neuromyotonia (NMT) is an autoimmune condition frequently associated with anti-contactin-associated-protein-like-2 (Caspr2) antibodies. NMT can occur as a paraneoplastic disorder in patients with thymoma, alone or in combination with Myasthenia Gravis (MG). Recently, antibodies against netrin-1-receptors (DCC and UNC5A) have been reported as predictors of thymoma in 6/9 patients with concomitant NMT and MG. We aimed to clinically characterize a large cohort of patients with thymoma-associated MG, and to explore serological correlation of NMT symptoms. Methods: 268 consecutive patients with thymoma-associated MG were retrospectively collected. NMT was defined as muscle twitching/cramps in at least 2 skeletal districts. Patients with NMT(23) were screened for anti-neuronal antibodies by immunohistochemistry on rat brain and cell based assay. Results: 23/268 patients developed NMT symptoms (muscle twitching, 3; cramps, 3, or both, 17). Overall, 33/268 patients with thymoma had a tumor recurrence, which was more frequent in those with (8/23) vs those without NMT (25/245, p=0.003). NMT onset preceded the tumor recurrence in 5/6 patients. In univariate analysis predictors of thymoma recurrence were younger age at thymectomy (odds ratio-OR:0.95, confidence interval-CI:0.93-0.97), Masaoka staging (OR:10.73, CI:2.38-48.36) and NMT (OR:4.69, CI:1.76-12.46). 6 patients with NMT had anti-neuronal antibodies (patient#1: Caspr2; patient#2: AMPAR; patient#3: DCC; patient#4: LGI1; patient#5: Caspr2+LGI1+DCC+UNC5A; patient#6: Caspr2+LGI1+DCC). Thymoma recurrence was found less frequently in negative (3/17) vs positive patients with NMT (4/6, #1, #2, #5 and #6; p=0.045). Conclusion: The occurrence of NMT symptoms in patients with thymoma-associated MG can predict tumor recurrence, and warrants a closer oncologic follow-up. Anti-neuronal surface autoantibodies may be useful to further stratify the recurrence risk. Disclosure: This work was funded by the ‘Ricerca finalizzata ministeriale 2015-2017’ provided by the Italian ministry of health

Hippocampal necrosis and hippocampal sclerosis in cats is a neuropathological entity which is a major concern in feline epilepsy. The aim of our study was to identify associated pathologic brain lesions possibly serving as aetiological triggers in this condition. Therefore, the formalin-fixed and paraffin waxembedded brain tissue of 35 cats diagnosed with hippocampal necrosis or sclerosis was examined retrospectively. In 26 cats inflammatory infiltrates could be found in the hippocampus or adjacent brain regions. Fifteen out of these animals demonstrated mild to moderate infiltrations by lymphocytes and complement deposition in the hippocampus similar to human limbic encephalitis, seven showed unspecific, predominantly non-suppurative inflammation, and two demonstrated suppurative inflammation of the hippocampus or adjacent brain regions. Additionally, one cat was diagnosed with central nervous manifestation of feline infectious peritonitis virus and another one with cerebral Toxoplasma gondii infection. Intracranial neoplasia was present in five cases altogether. Three of them comprised meningioma which was present additionally to lesions resembling limbic encephalitis in two cases, and a dentate gyrus alteration in one case. The other two tumour-associated cases comprised oligodendroglioma. Structural alterations of the dentate gyrus together with hippocampal sclerosis were encountered in three cases in total. Besides the case associated with a meningioma, one case demonstrated lesions resembling limbic encephalitis. A vascular infarct in the temporal lobe was encountered in one cat. In four cases no lesions other than hippocampal necrosis or sclerosis were found. The involvement of feline immunodeficiency virus infections, which may be able to produce hippocampal lesions, was not encountered in the cats examined.

Commercially available antibodies that bind to the human muscle acetylcholine receptor (ACHR) have been validated previously for flow cytometric use ( Keefe et al., 2009 ; Leite et al., 2008 ; Lozier et al., 2015 ). Despite a multitude of commercially available antibodies to other nicotinic ACHRs, validation in a wide variety of immunoassay formats is lacking; when studied, a large proportion of these antibodies have been deemed not fit for most research purposes ( Garg and Loring, 2017 ). We have recently described a flow cytometric immunomodulation assay for the diagnosis of Autoimmune Autonomic Ganglionopathy (AAG) ( Urriola et al., 2021 ) that utilises the monoclonal antibody mab35( Urriola et al., 2021 ) which is specific for ganglionic ACHR (gnACHR) that contain α3 subunits ( Vernino et al., 1998 ). Other fluorescent ligands for α3-gnACHR have not been validated for flow cytometric use. We investigated 7 commercially sourced antibodies and 3 synthetic fluorescent novel conotoxins purported to specifically bind to the extracellular domains of the gnACHR, and compared the results to staining by mab35, using flow cytometry with the neuroblastoma cell line IMR-32. We also evaluated the degree of non-specific binding by depleting the cell membrane of the relevant acetylcholine receptor with a pre-incubation step involving the serum from a patient with Autoimmune Autonomic Ganglionopathy containing pathogenic antibodies to the ganglionic acetylcholine receptor. None of the assessed conotoxins, and only one antibody (mab35) was found to perform adequately in flow cytometric staining of the native ganglionic acetylcholine receptor.

The appearance of a paraneoplastic neurological disorder (PND) with Hu-antibodies, often before tumour detection, together with spontaneous tumour regression in a few patients, suggests that immune responses to HuD, possibly mediated by cytotoxic T-cells, could be beneficial to the patient.1 Nevertheless, in previous retrospective studies, survival in Hu-antibody-associated PNDs (Hu-Ab/PNDs) in general was similar to those in patients with small-cell lung cancer (SCLC) without neurological illness.2 3 Here we studied, for the first time prospectively, tumour outcomes in a large series of patients with Hu-Ab/PNDs, comparing with contemporaneous patients with SCLC without neurological symptoms. ### Patients Written consent was obtained from all patients. From July 2012 to June 2015 prospectively we collected all serum samples that were positive for Hu-antibodies at Oxford University Hospitals as part of routine diagnostic testing via referral from any of England’s 152 acute hospital trusts. Diagnostic categorisation of associated PNDs was agreed between the research team and the referring physician, in line with published diagnostic criteria.4 For survival comparisons, contemporaneous control data and pre-treatment serum samples were obtained prospectively from 245 patients with SCLC, without PNDs, from the Nottingham Trent region over the same time period. Serum samples were stored at −80°C and retested for Hu and SOX2 antibodies by ELISA, and paraneoplastic antibodies tested on frozen rat cerebellum with positive results confirmed using a multi-line blot (Ravo Diagnostika, Freiburg, Germany) (see online supplemental methods). ### Supplementary data [jnnp-2021-326067supp001.pdf] ### Statistical analysis Survival statistics from date of SCLC diagnosis in PND and control groups were calculated using log-rank tests, and differences in cancer survival according to presence of PNDs and Hu-antibodies were evaluated using a Cox proportional hazards model. ### Patients with Hu-antibody PNDs and SCLC controls One …

Objective: To optimize sensitivity and disease specificity of a myelin oligodendrocyte glycoprotein (MOG) antibody assay. Methods: Consecutive sera (n 5 1,109) sent for aquaporin-4 (AQP4) antibody testing were screened for MOG antibodies (Abs) by cell-based assays using either full-length human MOG (FL-MOG) or the short-length form (SL-MOG). The Abs were initially detected by Alexa Fluor goat anti-human IgG (H 1 L) and subsequently by Alexa Fluor mouse antibodies to human IgG1. Results: When tested at 1:20 dilution, 40/1,109 sera were positive for AQP4-Abs, 21 for SLMOG, and 180 for FL-MOG. Only one of the 40 AQP4-Ab–positive sera was positive for SLMOG-Abs, but 10 (25%) were positive for FL-MOG-Abs (p 5 0.0069). Of equal concern, 48% (42/88) of sera from controls (patients with epilepsy) were positive by FL-MOG assay. However, using an IgG1-specific secondary antibody, only 65/1,109 (5.8%) sera were positive on FL-MOG, and AQP4-Ab– positive and control sera were negative. IgM reactivity accounted for the remaining anti-human IgG (H 1 L) positivity toward FL-MOG. The clinical diagnoses were obtained in 33 FL-MOG–positive patients, blinded to the antibody data. IgG1-Abs to FL-MOG were associated with optic neuritis (n 5 11), AQP4-seronegative neuromyelitis optica spectrum disorder (n 5 4), and acute disseminated encephalomyelitis (n 5 1). All 7 patients with probable multiple sclerosis (MS) were MOG-IgG1 negative. Conclusions: The limited disease specificity of FL-MOG-Abs identified using Alexa Fluor goat antihuman IgG (H 1 L) is due in part to detection of IgM-Abs. Use of the FL-MOG and restricting to IgG1-Abs substantially improves specificity for non-MS demyelinating diseases. Classification of evidence: This study provides Class II evidence that the presence of serum IgG1- MOG-Abs in AQP4-Ab–negative patients distinguishes non-MS CNS demyelinating disorders from MS (sensitivity 24%, 95% confidence interval [CI] 9%–45%; specificity 100%, 95% CI 88%–100%). Neurol Neuroimmunol Neuroinflamm 2015;2:e89; doi: 10.1212/ NXI.0000000000000089

See Scheffer (doi:10.1093/brain/awz208) for a scientific commentary on this article. In a prospective population-based cohort study, Symonds et al. perform high-throughput genetic testing in children presenting with seizures before 3 years of age, and provide incidence estimates for the most common single-gene epilepsies. One quarter of cases are found to have a genetic cause, and 80% of the genetic diagnoses are found to have potential treatment implications., Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children’s hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9–57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26–14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93–12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24–9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07–7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.

Serum antibodies that bind to the surface of neurons or glia are associated with a wide range of rare but treatable CNS diseases. In many, if not most instances, the serum levels are higher than CSF levels yet most of the reported attempts to reproduce the human disease in mice have used infusion of antibodies into the mouse cerebral ventricle(s) or intrathecal space. We used the intraperitoneal route and injected purified plasma IgG from either a CASPR2-antibody-positive patient (n = 10 mice) or healthy individual (n = 9 mice) daily for 8 days. Lipopolysaccharide was injected intraperitoneally on Day 3 to cause a temporary breach in the blood brain barrier. A wide range of baseline behaviours, including tests of locomotion, coordination, memory, anxiety and social interactions, were established before the injections and tested from Day 5 until Day 11. At termination, brain tissue was analysed for human IgG, CASPR2 and c-fos expression, lymphocyte infiltration, and neuronal, astrocytic and microglial markers. Mice exposed to CASPR2-IgG, compared with control-IgG injected mice, displayed reduced working memory during the continuous spontaneous alternation test with trends towards reduced short-term and long-term memories. In the open field tests, activities were not different from controls, but in the reciprocal social interaction test, CASPR2-IgG injected mice showed longer latency to start interacting, associated with more freezing behaviour and reduced non-social activities of rearing and grooming. At termination, neuropathology showed more IgG deposited in the brains of CASPR2-IgG injected mice, but a trend towards increased CASPR2 expression; these results were mirrored in short-term in vitro experiments where CASPR2-IgG binding to hippocampal neurons and to CASPR2-transfected HEK cells led to some internalization of the IgG, but with a trend towards higher surface CASPR2 expression. Despite these limited results, in the CASPR2-IgG injected mouse brains there was increased c-fos expression in the piriform-entorhinal cortex and hypothalamus, and a modest loss of Purkinje cells. There was also increased microglia density, morphological changes in both microglia and astrocytes and raised complement C3 expression on astrocytes, all consistent with glial activation. Patients with CASPR2 antibodies can present with a range of clinical features reflecting central, autonomic and peripheral dysfunction. Although the behavioural changes in mice were limited to social interactions and mild working-memory defects, the neuropathological features indicate potentially widespread effects of the antibodies on different brain regions.

Opsoclonus-myoclonus syndrome is a rare but serious neurological condition resulting in loss of control of eye movements, often accompanied by difficulties in posture and movement control with reports of sensory sensitivities potentially impacting on behavior. This pilot study characterizes the presence of atypical sensory behaviors in opsoclonus-myoclonus syndrome through questionnaire survey of a cohort of families. The Short Sensory Profile, Vineland Adaptive Behavior Scale, and Developmental Behaviour Checklist were distributed to 30 families; 16 were returned anonymously. Atypical sensory behaviors were identified in a large proportion (62.5%). Children reported as being more anxious showed greater sensitivity to auditory stimuli, U(14) 11, P = .026. This is consistent with recent recognition of more extensive disease neurocognitive effects in Opsoclonus-myoclonus syndrome. Further research is needed to increase understanding of the complex pathology of this disease and to provide indicators for sensory and behavioral as well as pharmacological interventions.

Key Points Questions Which specific targets of voltage-gated potassium channel–complex antibodies are found in acquired neuromyotonia, and are these antibodies associated with additional clinical features of tumors, pain, or autonomic or central disorders? Findings This cohort study combined with a patient-led survey found that antibodies to the extracellular aspects of leucine-rich glioma inactivated protein, contactin-associated protein 2, and contactin 2 were variably present in 45% of patients with neuromyotonia. Paresthesia and various pain manifestations were common in neuromyotonia, and the type and severity of pain were found to exert a substantial influence on quality of life. Meaning Antibodies to voltage-gated potassium channel–complex proteins are not found in all patients with neuromyotonia and do not individually relate to specific clinical features, but the presence of pain and its effects on quality of life need greater recognition., Importance Although acquired autoimmune neuromyotonia (NMT) is associated with voltage-gated potassium channel (VGKC)–complex antibodies, to date there has been no systematic study of autoantibodies to the specific antigens leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein 2 (CASPR2), and contactin 2 together with the full clinical syndrome, particularly pain and autonomic and central nervous system involvement. Objectives To study the full spectrum of clinical features and serum autoantibodies in patients with NMT, including the effects of pain on quality of life. Design, Setting, and Participants A cohort study of clinical features and serologic testing in 38 patients with electrophysiologically-confirmed NMT, reviewed clinically between February 2007 and August 2009, in the Universities of Sydney and Kagoshima and followed up across 2 to 4 years. Association of NMT with quality of life was researched in an independent, patient-led, online pain survey conducted from April 2012 to May 2012. Serologic analyses were performed in 2012, and final data analysis was performed in 2016. Main Outcomes and Measures Clinical data and scores on the modified Rankin Scale (mRS), which measures disability on a range of 0 to 6, with 0 indicating normal and 6 indicating death, before and after treatments were combined with CASPR2, LGI1, and contactin 2 antibody status. Results Among the 38-person NMT cohort, 25 (65.8%) were male and the median (range) age was 55 (12-85) years. Twenty-three (60.5%) were Japanese and 15 (39.5%) were of white race/ethnicity. Symptomatic treatments (mainly antiepileptic drugs) were used in most patients with mild disease (12 patients with mRS, This combined clinical cohort and survey study examines associations between neuromyotonia and voltage-gated potassium channel–complex–specific antibodies and the consequences of neuromyotonia for quality of life.

Objective To identify neuronal surface antibodies in opsoclonus myoclonus ataxia syndrome (OMAS) using contemporary antigen discovery methodology. Methods OMAS patient serum immunoglobulin G immunohistochemistry using age-equivalent rat cerebellar tissue was followed by immunoprecipitation, gel electrophoresis, and mass spectrometry. Data are available via ProteomeXchange (identifier PXD009578). This generated a list of potential neuronal surface cerebellar autoantigens. Live cell-based assays were used to confirm membrane-surface antigens and adsorb antigen-specific immunoglobulin Gs. The serologic results were compared to the clinical data. Results Four of the 6 OMAS sera tested bound rat cerebellar sections. Two of these sera with similar immunoreactivities were used in immunoprecipitation experiments using cerebellum from postnatal rat pups (P18). Mass spectrometry identified 12 cell-surface proteins, of which glutamate receptor δ2 (GluD2), a predominately cerebellar-expressed protein, was found at a 3-fold-higher concentration than the other 11 proteins. Antibodies to GluD2 were identified in 14/16 (87%) OMAS samples, compared with 5/139 (5%) pediatric and 1/38 (2.6%) adult serum controls (p < 0.0001), and in 2/4 sera from patients with neuroblastoma without neurologic features. Adsorption of positive OMAS sera against GluD2-transfected cells substantially reduced but did not eliminate reactivity toward cerebellar sections. Conclusion Autoantibodies to GluD2 are common in patients with OMAS, bind to surface determinants, and are potentially pathogenic.

To assess the clinical and immunologic findings in children with voltage-gated potassium channel (VGKC)-complex antibodies (Abs).Thirty-nine of 363 sera, referred from 2 pediatric centers from 2007 to 2013, had been reported positive (.100 pM) for VGKC-complex Abs. Medical records were reviewed retrospectively and the patients’ condition was independently classified as inflammatory (n 5 159) or noninflammatory (n 5 204). Positive sera (.100 pM) were tested/retested for the VGKC complex Ab–positive complex proteins LGI1 and CASPR2, screened for binding to live hippocampal neurons, and 12 high-titer sera (.400 pM) tested by radioimmunoassay for binding to VGKC Kv1 subunits with or without intracellular postsynaptic density proteins.VGKC-complex Abs were found in 39 children, including 20% of encephalopathies and 7.6% of other conditions (p 5 0.001). Thirty children had inflammatory conditions and 9 had noninflammatory etiologies but titers.400 pM (n512) were found only in inflammatory diseases (p , 0.0001). Four sera, including from 2 children with coexisting NMDA receptor Abs and one with Guillain-Barré syndrome and Abs to both LGI1 and CASPR2, bound to hippocampal neurons. None of the sera bound detectably to VGKC Kv1 subunits on live HEK cells, but 4 of 12 .400 pM sera immunoprecipitated VGKC Kv1 subunits, with or without postsynaptic densities, extracted from transfected cells.Positive VGKC-complex Abs cannot be taken to indicate a specific clinical syndrome in children, but appear to be a nonspecific biomarker of inflammatory neurologic diseases, particularly of encephalopathy. Some of the Abs may bind to intracellular epitopes on the VGKC subunits, or to the intracellular interacting proteins, but in many the targets remain undefined.

Objective: To determine the frequency and range of paraneoplastic neurologic disorders (PNDs) and neuronal antibodies in small cell lung carcinoma (SCLC). Methods: Two hundred sixty-four consecutive patients with biopsy-proven SCLC were recruited at the time of tumor diagnosis. All patients underwent full neurologic examination. Serum samples were taken prior to chemotherapy and analyzed for 15 neuronal antibodies. Thirty-eight healthy controls were analyzed in parallel. Results: PNDs were quite prevalent (n = 24, 9.4%), most frequently Lambert-Eaton myasthenic syndrome (3.8%), sensory neuronopathy (1.9%), and limbic encephalitis (1.5%). Eighty-seven percent of all patients with PNDs had antibodies to SOX2 (62.5%), HuD (41.7%), or P/Q VGCC (50%), irrespective of their syndrome. Other neuronal antibodies were found at lower frequencies (GABAb receptor [12.5%] and N-type VGCC [20.8%]) or very rarely (GAD65, amphiphysin, Ri, CRMP5, Ma2, Yo, VGKC complex, CASPR2, LGI1, and NMDA receptor [all Conclusions: The spectrum of PNDs is broader and the frequency is higher than previously appreciated, and selected antibody tests (SOX2, HuD, VGCC) can help determine the presence of an SCLC.

BACKGROUND AND OBJECTIVES: Pediatric encephalitis has a wide range of etiologies, clinical presentations, and outcomes. This study seeks to classify and characterize infectious, immune-mediated/autoantibody-associated and unknown forms of encephalitis, including relative frequencies, clinical and radiologic phenotypes, and long-term outcome. METHODS: By using consensus definitions and a retrospective single-center cohort of 164 Australian children, we performed clinical and radiologic phenotyping blinded to etiology and outcomes, and we tested archived acute sera for autoantibodies to N-methyl-D-aspartate receptor, voltage-gated potassium channel complex, and other neuronal antigens. Through telephone interviews, we defined outcomes by using the Liverpool Outcome Score (for encephalitis). RESULTS: An infectious encephalitis occurred in 30%, infection-associated encephalopathy in 8%, immune-mediated/autoantibody-associated encephalitis in 34%, and unknown encephalitis in 28%. In descending order of frequency, the larger subgroups were acute disseminated encephalomyelitis (21%), enterovirus (12%), Mycoplasma pneumoniae (7%), N-methyl-D-aspartate receptor antibody (6%), herpes simplex virus (5%), and voltage-gated potassium channel complex antibody (4%). Movement disorders, psychiatric symptoms, agitation, speech dysfunction, cerebrospinal fluid oligoclonal bands, MRI limbic encephalitis, and clinical relapse were more common in patients with autoantibodies. An abnormal outcome occurred in 49% of patients after a median follow-up of 5.8 years. Herpes simplex virus and unknown forms had the worst outcomes. According to our multivariate analysis, an abnormal outcome was more common in patients with status epilepticus, magnetic resonance diffusion restriction, and ICU admission. CONCLUSIONS: We have defined clinical and radiologic phenotypes of infectious and immune-mediated/autoantibody-associated encephalitis. In this resource-rich cohort, immune-mediated/autoantibody-associated etiologies are common, and the recognition and treatment of these entities should be a clinical priority.

Objective: To search for antibodies against neuronal cell surface proteins. Methods: Using immunoprecipitation from neuronal cultures and tandem mass spectrometry, we identified antibodies against the α1 subunit of the γ-aminobutyric acid A receptor (GABA A R) in a patient whose immunoglobulin G (IgG) antibodies bound to hippocampal neurons. We searched 2,548 sera for antibodies binding to GABA A R α, β, and γ subunits on live HEK293 cells and identified the class, subclass, and GABA A R subunit specificities of the positive samples. Results: GABA A R-Abs were identified in 40 of 2,046 (2%) referred sera previously found negative for neuronal antibodies, in 5/502 (1%) previously positive for other neuronal surface antibodies, but not in 92 healthy individuals. The antibodies in 40% bound to either the α1 (9/45, 20%) or the γ2 subunits (9/45, 20%) and were of IgG1 (94%) or IgG3 (6%) subclass. The remaining 60% had lower antibody titers ( p = 0.0005), which were mainly immunoglobulin M (IgM) ( p = 0.0025), and showed no defined subunit specificity. Incubation of primary hippocampal neurons with GABA A R IgG1 sera reduced surface GABA A R membrane expression. The clinical features of 15 patients (GABA A R α1 n = 6, γ2 n = 5, undefined n = 4) included seizures (47%), memory impairment (47%), hallucinations (33%), or anxiety (20%). Most patients had not been given immunotherapies, but one with new-onset treatment-resistant catatonia made substantial improvement after plasma exchange. Conclusions: The GABA A R α1 and γ2 are new targets for antibodies in autoimmune neurologic disease. The full spectrum of clinical features, treatment responses, correlation with antibody specificity, and in particular the role of the IgM antibodies will need to be assessed in future studies.

Gestational transfer of maternal antibodies against fetal neuronal proteins may be relevant to some neurodevelopmental disorders, but until recently there were no proteins identified. We recently reported a fivefold increase in CASPR2-antibodies in mid-gestation sera from mothers of children with intellectual and motor disabilities. Here, we exposed mice in utero to purified IgG from patients with CASPR2-antibodies (CASPR2-IgGs) or from healthy controls (HC-IgGs). CASPR2-IgG but not HC-IgG bound to fetal brain parenchyma, from which CASPR2-antibodies could be eluted. CASPR2-IgG exposed neonates achieved milestones similarly to HC-IgG exposed controls but, when adult, the CASPR2-IgG exposed progeny showed marked social interaction deficits, abnormally located glutamatergic neurons in layers V–VI of the somatosensory cortex, a 16% increase in activated microglia, and a 15–52% decrease in glutamatergic synapses in layers of the prefrontal and somatosensory cortices. Thus, in utero exposure to CASPR2-antibodies led to permanent behavioral, cellular, and synaptic abnormalities. These findings support a pathogenic role for maternal antibodies in human neurodevelopmental conditions, and CASPR2 as a potential target. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1751-5) contains supplementary material, which is available to authorized users.

Summary GABAB receptor (GABABR) autoantibodies have been detected in the serum of immunotherapy‐responsive patients with autoimmune encephalitis. This study aimed to investigate the effect of immunoglobulin G (IgG) from a patient with GABABR antibodies on primary neuronal cultures and acute slices of entorhinal cortex. Primary hippocampal neuronal cultures were incubated with serum immunoglobulin from patients with GABABR or AMPA receptor (AMPAR) antibodies for up to 72 h to investigate their effect on receptor surface expression. Whole‐cell patch‐clamp recordings from layer III pyramidal cells of the medial entorhinal cortex were used to examine the effect on neuronal activity. GABABR surface expression was unaltered by incubation with GABABR antibodies. By contrast, after 24 h application of AMPAR antibodies, AMPARs were undetectable. However, acute application of GABABR IgG decreased both the duration of network UP states and the spike rate of pyramidal cells in the entorhinal cortex. GABABR antibodies do not appear to affect GABABRs by internalization but rather reduce excitability on the medial temporal lobe networks. This unusual mechanism of action may be exploited in rational drug development strategies.

Faciobrachial dystonic seizures (FBDS) are the first adult-onset autoantibody-mediated epilepsy. Thompson et al. describe 103 patients with FBDS, and show that seizures are responsive to immunotherapy, with early seizure cessation reducing long-term disability and preventing cognitive impairment. Potential pathogenic mechanisms include complement fixation and LGI1-ADAM22 complex internalisation., Faciobrachial dystonic seizures and limbic encephalitis closely associate with antibodies to leucine-rich glioma-inactivated 1 (LGI1). Here, we describe 103 consecutive patients with faciobrachial dystonic seizures and LGI1 antibodies to understand clinical, therapeutic and serological differences between those with and without cognitive impairment, and to determine whether cessation of faciobrachial dystonic seizures can prevent cognitive impairment. The 22/103 patients without cognitive impairment typically had normal brain MRI, EEGs and serum sodium levels (P < 0.0001). Overall, cessation of faciobrachial dystonic seizures with antiepileptic drugs alone occurred in only 9/89 (10%) patients. By contrast, 51% showed cessation of faciobrachial dystonic seizures 30 days after addition of immunotherapy (P < 0.0001), with earlier cessation in cognitively normal patients (P = 0.038). Indeed, expedited immunotherapy (P = 0.031) and normal cognition (P = 0.0014) also predicted reduced disability at 24 months. Furthermore, of 80 patients with faciobrachial dystonic seizures as their initial feature, 56% developed cognitive impairment after 90 days of active faciobrachial dystonic seizures. Whereas only one patient developed cognitive impairment after cessation of faciobrachial dystonic seizures (P < 0.0001). All patients had IgG4-LGI1 antibodies, but those with cognitive impairment had higher proportions of complement-fixing IgG1 antibodies (P = 0.03). Both subclasses caused LGI1-ADAM22 complex internalization, a potential non-inflammatory epileptogenic mechanism. In summary, faciobrachial dystonic seizures show striking time-sensitive responses to immunotherapy, and their cessation can prevent the development of cognitive impairment.

We thank Feras Mustafa, and Frank Leypoldt and colleagues for their comments on our study about the prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis.1

Introduction Merkel cell carcinoma is a rare cutaneous, aggressive tumor. Although it shares many neuroendocrine features with small cell lung carcinoma, it has only occasionally been reported with paraneoplastic neurological syndromes. Methods A healthy 67-year-old man developed acute ataxia, vertigo, and nausea. Subsequently he also developed dysarthria, diplopia, xerostomia, fatigability and progressive anorexia. He underwent a full diagnostic workup and was found to have a high titer of voltage-gated calcium channel antibodies in serum and cerebrospinal fluid, neurophysiological findings compatible with Lambert-Eaton myasthenia and neurological signs compatible with cerebellar degeneration. Results A positron emission tomography study revealed a hypermetabolic lesion in the axilla, subsequently biopsied and consistent with Merkel cell carcinoma. Conclusions In most previous reports, neurological symptoms preceded the Merkel cell carcinoma diagnosis, and the primary localization was in lymph nodes. This tumor should be considered in patients with paraneoplastic syndrome, and particularly Lambert-Eaton myasthenia after exclusion of small cell lung carcinoma. Muscle Nerve 56: 998–1000, 2017

Summary Background Psychosis is a common presenting feature in antibody-mediated encephalitis, for which prompt recognition and treatment usually leads to remission. We aimed to investigate whether people with circumscribed schizophrenia-like illnesses have such antibodies—especially antibodies against the N-methyl-D-aspartate receptor (NMDAR)—more commonly than do healthy controls. Methods We recruited patients aged 14–35 years presenting to any of 35 mental health services sites across England with first-episode psychosis, less than 6 weeks of treatment with antipsychotic medication, and a score of 4 or more on at least one selected Positive and Negative Syndrome Scale (PANSS) item. Patients and controls provided venous blood samples. We completed standardised symptom rating scales (PANSS, ACE-III, GAF) at baseline, and tested serum samples for antibodies against NMDAR, LGI1, CASPR2, the GABA A receptor, and the AMPA receptor using live cell-based assays. Treating clinicians assessed outcomes of ICD diagnosis and functioning (GAF) at 6 months. We included healthy controls from the general population, recruited as part of another study in Cambridge, UK. Findings Between Feb 1, 2013, and Aug 31, 2014, we enrolled 228 patients with first-episode psychosis and 105 healthy controls. 20 (9%) of 228 patients had serum antibodies against one or more of the neuronal cell surface antibodies compared with four (4%) of 105 controls (unadjusted odds ratio 2·4, 95% CI 0·8–7·3). These associations remained non-significant when adjusted for current cigarette smoking, alcohol consumption, and illicit drug use. Seven (3%) patients had NMDAR antibodies compared with no controls (p=0·0204). The other antibodies did not differ between groups. Antibody-positive patients had lower PANSS positive, PANSS total, and catatonia scores than did antibody-negative patients. Patients had comparable scores on other PANSS items, ACE-III, and GAF at baseline, with no difference in outcomes at 6 months. Interpretation Some patients with first-episode psychosis had antibodies against NMDAR that might be relevant to their illness, but did not differ from patients without NMDAR antibodies in clinical characteristics. Our study suggests that the only way to detect patients with these potentially pathogenic antibodies is to screen all patients with first-episode psychosis at first presentation. Funding Medical Research Council.

Summary Purpose Autoantibodies to specific neurologic proteins are associated with subacute onset encephalopathies, which often present with seizures that are poorly controlled by conventional antiepileptic drugs (AEDs). Previous cross-sectional studies have found specific neurologic antibodies in a small proportion of people with established epilepsy, but these investigations have seldom included patients with recent diagnosis. Methods We screened two large epilepsy cohorts to investigate the prevalence of multiple autoantibodies in adult patients with either established or newly diagnosed, untreated epilepsy. Key Findings Eleven percent of patients had antibodies to one or more antigen: voltage-gated potassium channel (VGKC) complex proteins (5%), glycine receptors (3%), and glutamic acid decarboxylase (GAD) and N-methyl-d-aspartate (NMDA) receptors (1.7% each). There was no difference in the prevalence of antibodies, individually or collectively, between patients with established and newly diagnosed epilepsy or with generalized or focal epilepsy. There was, however, a significantly higher prevalence of positive antibody titers in patients with focal epilepsy of unknown cause than in those with structural/metabolic focal epilepsy (14.8% vs. 6.3%; p

Objective:To establish whether improved tumor survival in patients with Lambert-Eaton myasthenic syndrome (LEMS) and small-cell lung cancer (SCLC) was due to known prognostic risk factors or an effect of LEMS independently, perhaps as a result of circulating factors.Methods:We undertook a prospective observational cohort study of patients with LEMS attending Nottingham University Hospitals, UK, or via the British Neurological Surveillance Unit. In parallel, patients with a new diagnosis of biopsy-proven SCLC were enrolled, examined for neurologic illness, and followed up until death or study end.Results:Between May 2005 and November 2014, we recruited 31 patients with LEMS and SCLC and 279 patients with SCLC without neurologic illness. Allowing for known SCLC survival prognostic factors of disease extent, age, sex, performance status, and sodium values, multivariate Cox regression analysis showed that the presence of LEMS with SCLC conferred a significant survival advantage independently of the other prognostic variables (hazard ratio 1.756, 95% confidence interval 1.137–2.709, p = 0.011).Conclusions:Improved SCLC tumor survival seen in patients with LEMS and SCLC may not be due solely to lead time bias, given that survival advantage remains after allowing for other prognostic factors and that the same degree of survival advantage is not seen in patients with paraneoplastic neurologic syndromes other than LEMS presenting before SCLC diagnosis.

Introduction The Lambert Eaton myasthenic syndrome (LEMS) is a paraneoplastic disorder associated with raised serum voltage-gated calcium channel (VGCC) antibodies in patients with small cell lung cancer (SCLC). VGCC can also be found in patients with SCLC and cerebellar ataxia. This was a prospective study to assess the incidence of clinical and subclinical LEMS or other neurologic disease in patients with SCLC. Patients and Methods Sixty-three unselected patients with cytologically or histologically confirmed SCLC consented to participate. Pretreatment assessment included a neurologic symptom questionnaire, examination for physical signs of LEMS or ataxia, measurement of serum titers of antibodies to P/Q-type VGCCs by radioimmunoassay in all patients and electrophysiological examination where appropriate. Results Neurologic symptoms unrelated to LEMS occurred in 26% of patients. Five patients (8%) had raised serum VGCC antibodies (range, 69–1553 pM/l) diagnostic of LEMS, two (3%) of whom had LEMS on clinical and electrophysiological grounds. Both also had mild cerebellar ataxia. There was no association between serum VGCC antibody titer and survival. Conclusion Routine measurement of VGCC antibodies in patients without clinical LEMS is unlikely to assist either in management of SCLC or in assessment of prognosis.

Summary Background Over the last few years autoantibodies against neuronal proteins have been identified in several forms of autoimmune encephalitis and epilepsy. NMDA receptor (NMDAR) and voltage gated potassium channel (VGKC) complex antibodies are mainly associated with limbic encephalitis (LE) whereas glutamic acid decarboxylase antibodies (GADA) and anticardiolipin (ACL) antibodies are more commonly detected in patients with chronic epilepsy. Clinical features vary between these antibodies suggesting the specificity of different neuronal antibodies in seizures. Methods Serum samples of 14 GADA positive and 24 ACL positive patients with refractory epilepsy were analyzed for the presence of VGKC or NMDAR antibodies. Results No positive VGKC or NMDAR antibodies were found in these patients. Conclusions The results confirm the different significance of these neuronal antibodies in seizure disorders. Different autoantibodies have different significance in seizures and probably have different pathophysiological mechanisms of actions.

Purpose Hu antibodies previously have been associated with longer survival of patients with small-cell lung cancer (SCLC). Voltage-gated calcium channel (VGCC) antibodies play a pathogenic role in Lambert Eaton myasthenic syndrome, which is also associated with SCLC. These antibodies may reduce tumor growth in patients with the neurologic disease, but it is not clear whether they provide prognostic information in those without neurologic symptoms. Patients and Methods Two hundred patients with SCLC (age 39 to 79 years; mean, 62.3 years; 129 males and 71 females) receiving chemotherapy were studied for the presence of Hu and VGCC antibodies. Sera were examined for Hu antibodies by an in vitro transcription-translation–based immunoprecipitation technique and by immunohistochemistry/dot blot. VGCC (P/Q subtype) antibodies were detected by radioimmunoassay. Survival analysis was used to analyze the data. Results Hu antibodies were detected in 51 of 200 patients (25.5%) by in vitro transcription-translation–based immunoprecipitation and in 37 of 200 patients (18.5%) by immunohistochemistry or dot blot, whereas VGCC antibodies were detected in only 10 of 200 patients (5%). The presence of Hu antibodies did not correlate with VGCC antibodies, and there was no association between Hu or VGCC antibodies and the extent of disease or survival. Conclusion Hu and VGCC antibodies are found in a proportion of SCLC patients, irrespective of neurologic symptoms, but their presence does not correlate with the prognosis of the SCLC.

Objective: A study was undertaken to describe the clinical spectrum, voltage-gated potassium channel (VGKC) complex antibody specificities, and central nervous system localization of antibody binding in 29 patients diagnosed with Morvan syndrome (MoS). Methods: Clinical data were collected using questionnaires. Radioimmunoassay, cell-based assays, and mouse brain immunohistochemistry were used to characterize the serum antibodies. Results: Neuromyotonia (100%), neuropsychiatric features (insomnia 89.7%, confusion 65.5%, amnesia 55.6%, hallucinations 51.9%), dysautonomia (hyperhidrosis 86.2%, cardiovascular 48.3%), and neuropathic pain (62.1%) were the most common manifestations. A total of 93.1% of MoS patients were male. VGKC-complex antibodies were present in 23 of 29 (79%) MoS patients at referral; 24 of 27 available sera had CASPR2, LGI1, or both CASPR2 and LGI1 antibodies (3 also with contactin-2 antibodies). CASPR2 antibodies were generally higher titer than LGI1 antibodies. Tumors (41.4%), mainly thymomas, were associated with CASPR2 antibodies and a poor prognosis, whereas LGI1 antibodies were associated with serum hyponatremia. In brain tissue regions including the hypothalamus, raphe, and locus coeruleus, commercial antibodies to LGI1 bound to neuronal cell bodies including the antidiuretic hormone-secreting and orexin-secreting hypothalamic neurons, whereas CASPR2 commercial antibodies bound more often to the neuropil. MoS antibodies bound similarly, but there was evidence of additional antibodies in some sera that were not adsorbed by LGI1- or CASPR2-expressing cells and bound to mouse Caspr2−/− tissue. Interpretation: MoS is clinically distinct from other VGKC-complex antibody-associated conditions, and usually is associated with high-titer CASPR2 antibodies, often accompanied by lower-titer LGI1 antibodies. CASPR2 and LGI1 antibodies bind to multiple brain regions, which helps to explain the multifocal clinical features of this disease, but other antibodies are likely to play a role in some patients and need to be characterized in future studies. ANN NEUROL 2012

A 5-year-old, female client-owned cat presented with acute onset of focal epileptic seizures with orofacial twitching and behavioural changes. Magnetic resonance imaging showed bilateral temporal lobe hyperintensities and the EEG was consistent with ictal epileptic seizure activity. After antiepileptic and additional corticosteroid treatment, the cat recovered and by 10 months of follow-up was seizure-free without any problem. Retrospectively, antibodies to LGI1, a component of the voltage-gated potassium channel-complex, were identified. Feline focal seizures with orofacial involvement have been increasingly recognised in client-owned cats, and autoimmune limbic encephalitis was recently suggested as a possible aetiology. This is the first report of EEG, MRI and long-term follow-up of this condition in cats which is similar to human limbic encephalitis.

Background Relatively few studies have searched for potentially pathogenic antibodies in non-paraneoplastic patients with cerebellar ataxia. Methods and Results We first screened sera from 52 idiopathic ataxia patients for binding of serum IgG antibodies to cerebellar neurons. One strong-binding serum was selected for immunoprecipitation and mass spectrometry, which resulted in the identification of contactin-associated protein 2 (CASPR2) as a major antigen. CASPR2 antibodies were then found by a cell-based assay in 9/88 (10%) ataxia patients, compared to 3/144 (2%) multiple sclerosis or dementia controls (p=0.011). CASPR2 is strongly expressed in the cerebellum, only partly in association with voltage-gated potassium channels. Conclusions Prospective studies are now needed to see whether identification of CASPR2 antibodies has relevance for the diagnosis and treatment of idiopathic cerebellar ataxia.

Objective: To determine the prevalence of serum antibodies to the ionotropic glutamate receptor 3 (GluR3) in patients with Rasmussen encephalitis (RE), a severe epileptic disorder, and to compare with serum from control subjects and patients with intractable epilepsy (IE). Methods: The authors looked for serum immunoglobulin (Ig) G antibodies to GluR3 in 30 patients with RE, including two patients who had plasma exchange and 12 who had been treated with IV Igs with varying results, and 49 patients with IE and 23 healthy individuals, using ELISA with GluR3B peptide, Western blot analysis of recombinant full-length GluR3, immunoprecipitation of [ 35 S]- and [ 125 I]-labeled GluR3 extracellular domains, immunohistochemistry on rat brain sections, and electrophysiology of GluR3 expressed in Xenopus oocytes. Results: Low levels of antibodies to the GluR3B peptide were detected using ELISA in only 4 of the 79 patients with epilepsy (2 with RE and 2 with IE); binding to GluR3B in other sera was shown to be nonspecific. One other patient with IE had antibodies to recombinant GluR3 on Western blot analysis. However, none of the sera tested precipitated either the [ 35 S]- or the [ 125 I]-labeled GluR3 domains; none bound to rat brain sections in a manner similar to rabbit antibodies to GluR3; and none of the nine sera tested affected the electrophysiologic function of GluR3. Conclusions: GluR3 antibodies were only infrequently found in Rasmussen encephalitis or intractable epilepsy.

Autoantibodies that bind to voltage-gated potassium-channel complex proteins (VGKC-complex antibodies) occur frequently in adults with limbic encephalitis presenting with cognitive impairment and seizures. Recently, VGKC-complex antibodies have been described in a few children with limbic encephalitis, and children with unexplained encephalitis presenting with status epilepticus. We report a case of infantile-onset epileptic spasms and developmental delay compatible with epileptic encephalopathy. Our patient was a female infant, aged 4 months at presentation. She had evidence of immune activation in the central nervous system with elevated cerebrospinal fluid neopterin and mirrored oligoclonal bands, which prompted testing for autoantibodies. VGKC-complex antibodies were elevated (201 pmol/L, normal

OBJECTIVES: To determine the prognosis in patients with Lambert-Eaton myasthenic syndrome (LEMS) without small cell lung cancer (SCLC), and to analyse longitudinal clinical, electrophysiological, and immunological data on each patient to establish prognostic factors for long term outcome. METHODS: The retrospective and part prospective study of 47 patients with LEMS was undertaken from data recorded during visits to a specialist neuromuscular clinic. Serial measurements of muscle strength score in shoulder abduction, elbow extension and hip flexion, compound muscle action potential (CMAP) amplitude, and postcontraction increment in abductor digiti minimi (ADM), and anti-P/Q-type voltage gated calcium channel (VGCC) antibody titre were made at each visit. RESULTS: Muscle strength scores were improved in 88% of patients after a median duration of immunosuppressive treatment of 6 years (range 1.3 to 17 years); anti-VGCC antibody titres fell in 52% after treatment; and mean resting CMAP amplitude improved from 2.7 mV initially to 8.8 mV after 2 years of treatment p

Voltage-gated potassium channel complex (VGKC-complex) antibody (Ab) encephalitis is a well-recognized form of limbic encephalitis in humans, usually occurring in the absence of an underlying tumor. The patients have a subacute onset of seizures, magnetic resonance imaging findings suggestive of hippocampal inflammation, and high serum titers of Abs against proteins of the VGKC-complex, particularly leucine-rich, glioma-inactivated 1 (LGI1). Most patients are diagnosed promptly and recover substantially with immunotherapies; consequently, neuropathological data are limited. We have recently shown that feline complex partial cluster seizures with orofacial involvement (FEPSO) in cats can also be associated with Abs against VGKC-complexes/LGI1. Here we examined the brains of cats with FEPSO and compared the neuropathological findings with those in a human with VGKC-complex-Ab limbic encephalitis. Similar to humans, cats with VGKC-complex-Ab and FEPSO have hippocampal lesions with only moderate T-cell infiltrates but with marked IgG infiltration and complement C9neo deposition on hippocampal neurons, associated with neuronal loss. These findings provide further evidence that FEPSO is a feline form of VGKC-complex-Ab limbic encephalitis and provide a model for increasing understanding of the human disease.